Prion protein expression is required for prion infection and disease, but the roles of individual cell types in different infected organs is not yet clear. To approach this problem we have used transgenic mice expressing PrP in neurons only or in multiple cell types. After intraocular scrapie inoculation in mice expressing PrP in multiple cell types we noted degeneration of retinal cells and retinal microglial activation. In mice expressing PrP in neurons only, abnormal PrPres was detected by there was no retinal degeneration or microglial activation. This difference was not seen in brain tissue where activation and degeneration were extensive in both mouse strains. These results suggest that different microglial activation mechanisms occur after scrapie infection in retina and brain, and that PrP expression by retinal microglia might be an important factor in this process.[unreadable] [unreadable] Transgenic mice expressing two different alleles of deer prion protein were generated. Mice with the G96 allele were found to be susceptible to disease induced by 4 different pools of wild type CWD agent from deer or elk. In contrast S96 mice were resistant to all these pools. Since deer with the S96 allele are partially resistant to CWD it is possible that only a small number of CWD strain can infect such deer. Alternatively S96 deer might have other mechanisms of resistance to all strains of CWD. We are currently trying to distinguish between these possibilities by inoculating our mice with CWD agent derived from infected S96 deer.